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Cancer Res. 2013 Jul 15;73(14):4474-87. doi: 10.1158/0008-5472.CAN-12-3925. Epub 2013 May 29.

β-Catenin signaling is a critical event in ErbB2-mediated mammary tumor progression.

Author information

1
Goodman Cancer Centre, McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, Canada.

Abstract

Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying the aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model of ErbB2-driven tumor progression (ErbB2(KI) model) that recapitulates clinically relevant events, including selective amplification of the core erbB2 amplicon. By comparing the transcriptional profiles of ErbB2(KI) mammary tumors and human ERBB2-positive breast cancers, we show that ErbB2(KI) tumors possess molecular features of the basal subtype of ERBB2-positive human breast cancer, including activation of canonical β-catenin signaling. Inhibition of β-catenin-dependent signaling in ErbB2(KI)-derived tumor cells using RNA interference impaired tumor initiation and metastasis. Furthermore, treatment of ErbB2(KI) or human ERBB2-overexpressing tumor cells with a selective β-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires β-catenin signaling and can be therapeutically targeted by selective β-catenin/CBP inhibitors.

PMID:
23720052
DOI:
10.1158/0008-5472.CAN-12-3925
[Indexed for MEDLINE]
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